Counteracting Antimicrobial Resistance

Introduction

Antimicrobial resistance (AMR) stands as a formidable public health menace, casting a shadow over the twenty-first century.¹ This global crisis poses a substantial threat to the effectiveness of antibiotics and other antimicrobial agents, rendering once-treatable infections more resilient and potentially lethal. In general- widespread misuse of antibiotics, incompletion of course, overuse in food-chain (livestock and fish farming), inadequate infection control in healthcare facilities, poor hygiene, and very few new antibiotic discoveries are the leading causes of AMR.² Amongst all the nations, Bangladesh is one of the most susceptible to this burgeoning threat, where the challenges of AMR are particularly pronounced. Given that Bangladesh is within the top ten most densely populated countries, already plagued with innumerable healthcare infrastructural challenges, the alarming trend in AMR needs to be addressed at the earliest.

World Antimicrobial Resistance Awareness Week (WAAW) is observed annually from November 18th to 24th, emphasizing the critical importance of addressing AMR. The consistent and recurring theme, “Preventing Antimicrobial Resistance Together,” underscores the urgency of a concerted effort required across global communities to combat and deliver a solution to this pressing issue.³ The pledge “Go blue” serves as a symbolic call to action,⁴ encouraging individuals and organizations to unite in creating awareness, implementing responsible practices, and fostering a collective commitment to preserve the effectiveness of antimicrobial agents.

Urgent and coordinated efforts that includes the participation of healthcare, agriculture, and education sectors for a comprehensive approach are imperative to rein in the escalating threat of AMR in Bangladesh. Strengthening healthcare systems to enhance diagnostic capabilities, promoting judicious use of antimicrobials, and implementing stringent regulations on their sale and distribution are pivotal strategies.⁵ Additionally, relentless communication campaigns against random antibiotic usage and curbing the demand for unnecessary prescriptions will create widespread public awareness.

Global burden of AMR

The recent global burden of bacterial AMR is reflected in the escalating death rate per 100,000 associated with AMR-related infections. According to a study conducted in 2019, South Asia recorded a death rate of 75 per 100,000 while the highest number of 114.8 was reported from Western Sub-Saharan Africa.⁶ It is evident that our region is catching up. The gravity of the situation is underscored with predictive studies indicating that if appropriate measures are not taken right away, by the year 2050, mortality rate from AMR will be 10,000,000⁷ the same as from cancer for the same time. Multidrug-resistant frequencies of gram positive and gram negative bacteria like Enterococcus spp, Staphylococcus epidermidis and Staphylococcus aureus are around 91.4%, 64.9% and 38.8% respectively,⁸ which illustrates the growing challenge of treating infections from these bacteria.

Antimicrobial resistance is not new

Sir Alexander Fleming won the Nobel Prize in 1945 for his discovery of penicillin. The same year while giving an interview to The New York Times, he had warned that misuse of the drug could result in selection for resistant bacteria.⁹ True to this prediction, resistance began to emerge within 10 years of the wide scale introduction of penicillin. However, some experts believe that with a proper response to the current trend in antibiotic resistance, these drugs might once again serve their original purpose.

Drivers of Antimicrobial Resistance

AMR is propelled by a complex interplay of factors that span from various domains of human activity, healthcare practices to broader societal issues. The primary drivers of AMR encapsulate a range of challenges, each contributing to the alarming rise of resistant microbes.

Misuse and overuse of antimicrobial drugs is the first and foremost driver of AMR. In both clinical and agricultural settings, antibiotics are frequently prescribed without due consideration for proper diagnosis or dosage. Patients often self-medicate, and the agricultural sector employs antimicrobials as growth promoters for livestock. These practices create a selective pressure that encourages the survival of resistant strains, diminishing the efficacy of these crucial drugs.¹⁰

Poor access to clean water, sanitation, and hygiene (WASH) amplifies the problem. In environments lacking adequate sanitation facilities and clean water sources, the risk of infections surges. In the absence of proper hygiene practices, infections become more prevalent, leading to an increased demand for antimicrobials. The vicious cycle of infection and antibiotic use in unsanitary conditions escalates the likelihood of AMR emergence. Encouraging a simple yet effective practice like hand washing can significantly reduce the risk of cross transmission of infection.¹¹ The emphasis lies not on the quality of the soap but on the act itself. Whether using high-quality or average soap, the consistent habit of hand washing proves beneficial in preventing infections, highlighting the impactful nature of this basic hygiene measure.¹²

Poor infection control practices in healthcare facilities are a significant contributor of AMR. Inadequate measures to prevent the spread of infections within hospitals foster an environment where resistant strains can proliferate. The over reliance on antibiotics as a quick solution exacerbates this issue, as healthcare providers may resort to broad-spectrum antibiotics without precise diagnostic information.¹³

Lack of access to vaccinations in communities, hospitals, and schools compound the problem. Vaccines are crucial for preventing infectious diseases, reducing the need for antibiotic treatments.¹⁴ Insufficient vaccination coverage allows preventable diseases to persist, necessitating antibiotic interventions and subsequently contributing to the development of resistance.

The other reality adding to the overall bleak situation in fighting critical pathogen is the insufficient number of antibiotics currently in development. The pipeline for new antibiotics is not keeping pace with the evolving landscape of bacterial resistance.¹⁵ This scarcity of novel antimicrobial agents poses a grave threat as it limits the options available to clinicians facing increasingly resilient bacterial infections. The pharmaceutical industry faces challenges in developing new antibiotics due to financial considerations, scientific complexities, and regulatory hurdles, creating a concerning gap in our ability to address emerging infectious threats effectively.¹⁶

What can be done?

Establishment of antibiogram in hospitals: Utilizing an antibiogram empowers clinicians to discern patterns of antibiotic resistance among microorganisms.¹⁷ This insight enables targeted antibiotic prescription, allowing healthcare professionals to restrict the use of specific antibiotics in response to resistance trends. Notably, prolonged restrictions on antibiotic use may lead to a reversal in resistance, as microorganisms may lose their adaptive memory to resistance mechanisms.¹⁸ This strategic approach enhances antibiotic stewardship, optimizing treatment efficacy while minimizing the development of resistance in microbial populations over time.

Additionally, developing standardized treatment guidelines for antibiotic use for infectious diseases within individual hospitals is essential. These guidelines ensure judicious prescription practices, promoting responsible antibiotic usage and mitigating the risk of AMR.¹⁹

Awareness initiatives

Awareness initiatives are key in information dissemination and mobilizing communities on critical issues. Promoting proactive engagement through various communication activities will help bring focus to the imminent threat. Effective awareness initiatives that contribute to public education and advocacy are colorful rallies, poster presentations, social media campaigns and the AWaRe classification system.

Colorful rallies with participants parading through public spaces holding banners, signs, and lively displays reinforce the importance of AMR amongst people and is a great initiative for community engagement. The auditory and visual stimulation draws attention and piques the public’s interest.

Poster presentations are another impactful awareness initiative. Creative presentations can be strategically placed in high-traffic areas, such as healthcare facilities, educational institutions & community centers, to reach a diverse audience. Posters displaying information about the consequences of antimicrobial resistance, the importance of responsible antibiotic use and ways individuals can contribute to tackling the issue²⁰ help raise awareness.

Social media activation is currently the most interactive platform to reach millions with impactful audio-visual contents.

The AWaRe classification system, developed by the World Health Organization (WHO), is a tool that categorizes antibiotics into three g r o u p s — A c c e s s , Watch and Reserve —based on their rational use and the risk of resistance.²¹ This classification system underscores the need to prioritize “Reserve Group” antibiotics to preserve their effectiveness and educate healthcare professionals, policymakers, and the public about the prudent use of antibiotics.²²

Figure 1: The Aware Classification of Antibiotics²³

The “Reserve Group” Antibiotics

The classification of antibiotics into different groups is a strategic approach to managing the global challenge of AMR. The reserve antibiotics hold a distinct and critical position in the battle against infections caused by multi-drug-resistant organisms.²⁴ The name denotes that they are reserved as a last resort in the therapeutic arsenal for healthcare professionals.²⁵

Considered as the holy grail of antibiotics, “Reserve Group” are safe guarded for dire situations and deployed under stringent conditions to ensure their efficacy is preserved and not compromised for further resistance. Linezolid, Colistin, Ceftazidim, Tigecycline, Meropenam are some of the reserve group antibiotics that are prescribed when treatment options have narrowed down and a culture sensitivity report indicates sensitivity to only one of these particular antibiotics. It is strongly advised to conduct a thorough sensitivity analysis test for targeted treatment and to avoid using antibiotics from reserve group blindly. Prudent use, guided by accurate diagnostic information, remains crucial in preserving the effectiveness of reserve antibiotics in the healthcare landscape.²⁶

Scientific presentations are platforms to showcase research findings based on evidence to a diverse audience that includes healthcare professionals, policymakers, and the public.²⁷ Health care providers and policy advocates themselves need to delve deeper into the complexities surrounding antimicrobial use, resistance patterns, and the importance of responsible practices.

The above-mentioned initiatives and continuing medical education programs will contribute significantly to achieve the critical mass of collective effort to mitigate the escalating threat of AMR and promote informed decision-making in healthcare policies and practices.

Alternatives to Antibiotics

Although there are truly no alternatives to antibiotics yet to fight disease causing pathogens, the available options must still be explored to protect the effectiveness of antibiotics. Phage therapy is more than 100-years-old and was invented even before antibiotic discovery but is prohibited for use by the Food and Drug Administration in the USA on accounts of safety.²⁸ However, in some cases where nothing else works, it is still used as a compassionate therapy. It is not broad spectrum like antibiotic because one type of phage can only attack one specific bacteria by transferring its nucleic acid inside the bacteria and multiplying within it before killing it.²⁹

Vaccines against pathogens bolster the immune system which ultimately leads to decreased antibiotic consumptions. Plant derived phytochemicals can be used as alternatives to antibiotics. Probiotics are potential substitutes that competes with pathogenic bacteria in the body for nutrients, and produces antimicrobial substances, or initiates immune response.³⁰

The antimicrobial peptides (AMP) are small molecules of peptides that generate innate immunity in the host to battle against bacteria, fungi, viruses, and other parasites. Lysozyme is a naturally occurring AMP in the human body. AMPs act on multiple targets on plasma membrane and have potent activity on drug-resistant bacteria.³¹

CRISPR/Cas system- Pioneering Gene Editing Tool to Re-sensitize Bacteria to Antibiotics

The clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) constitute the CRISPR-Cas system which is an adaptive immune system in bacteria that identifies and protects it from foreign invading elements like viruses, phages, and plasmids.³² Bacteria snips out parts of the invader’s DNA by the Cas protein and keeps a bit of the DNA behind it for defending itself against the invader in future.³³

Antimicrobial resistance genes (ARG) are transferred among bacterial pathogens primarily through horizontal gene transfer (HGT) facilitated by Mobile Genetic Elements (MGEs) like plasmids and transposons. The HGT bypasses transfer via offspring and is the primary cause of AMR.³⁴

As an evolutionary process bacteria keep these genes to build resistance against antibiotics. Using bacteria’s innate CRISPR system to specifically target and cleave DNA sequences, the CRISPR-Cas system has evolved into a revolutionary gene-editing tool to identify ARGs with the objective to prevent and control AMR and re-sensitize drug-resistant bacteria.³⁵

The CRISPR-Cas9 genetic editing tool has been studied the most for the potential use to remove the ARGs¹ from the bacterial genome. Consisting of two parts- CRISPR is a long-scaffolded RNA that contains a predesigned 20 base long guide RNA (gRNA) along with the enzyme Cas9. This Cas9 is the main “molecular scissor” that can cut the two strands of DNA at specific locations of the genome to remove or add parts to the DNA. Before this action, the scaffolded part of CRISPR binds to DNA and the gRNA guides Cas9 to the right part of the genome to cut the right point.² Plasmids, extracellular vesicles, or phage are used as vectors to deliver the CRISPR-Cas9 into the bacteria to cleave the ARGs and make the bacteria sensitive to antibiotics again.¹

CRISPR-Cas12 is known to be used in disabling DNAs of superbugs and CRISPR-Cas13 is targeted to be used against DNA and RNA viruses. CRISPR-Cas was used in coronavirus detection kits,⁴ and the system can at the same time be used to inject desirable traits inducing genes in bacteria, like genes that can produce antimicrobial compounds.29 Gene editing tools are drawing more and more attention along with the advent of next generation gene sequencing technologies for targeted bactericidal management.⁵

Alternative options to antibiotics require more research but many are already promising to protect the therapeutic functions of antibiotics. Until the new therapeutics are proven with published protocols, it is advisable for countries like ours to remain prudent in antibiotic use.

Conclusion

The battle against AMR demands collaboration from various stakeholders, including healthcare providers, clinicians, pharmacologists, microbiologists, public health experts, nurses, drug sellers, pharmacists, pharmaceutical companies, and those involved in livestock management.

A multisectoral approach is paramount to address the multifaceted dimensions of AMR. Healthcare professionals play a central role in responsible antibiotic prescribing and patient education, while pharmacists and drug sellers contribute to ensuring adherence to prescription guidelines. Public health experts are crucial in formulating and implementing policies to regulate antibiotic use, and pharmaceutical companies bear responsibility for ethical drug production and innovation. Livestock management practices are also central to the problem as humans consume livestock that are treated with antibiotics, thus exacerbating the situation. Only through a unified approach can we hope to safeguard the efficacy of antimicrobial agents and ensure the continued effectiveness of these life-saving drugs.